How does the synaptic physiology of the cortical microcircuit regulate signal detection in striate cortical neurons? To approach this broad issue we analyze the synaptic basis of neuronal response structures at successive cortical stages and the connections that convey information from one cortical level to the next. The work is made possible by the advance of whole-cell recording in vivo, a technique that gives a highly resolved view of the postsynaptic events evoked during vision and allows intracellular staining of single neurons. AIM 1) The push-pull model of the simple receptive field holds that signals of reverse contrast have the opposite effect: bright stimuli presented to an on subregion evoke firing, whereas dark ones reduce activity. Two mechanisms have been proposed to account for the pull. One is passive withdrawal of excitation from the thalamus; the other is pharmacological analyses of the visual response. Further, we will determine if the push-pull model fully accounts for the spatial distribution of excitation and inhibition in the simple receptive field and if it predicts orientation tuning. AIM 2) Why do many complex cells respond poorly to the same stimuli that drive simple cells well? Our hypothesis is that the successive cortical stages employ different sets of synaptic mechanisms to regulate stimulus selectivity. If true, then complex cells that receive direct thalamic input should have response structures different from those of cells outside thalamic reach. This prediction is tested by comparing responses of cells in layer 4 with those in layer 2+3 to the same stereotyped stimulus. The anatomical substrate for information transfer from the first to second cortical stage is determined by labeling the connections extending from layer 4 to 2+3. A knowledge of how the brain operates in the everyday situation provides a standard against which to judge changes that occur in the course of various disorders, as well as a model system on which to test drugs developed to treat illness. From this perspective, the visual cortex is an obvious site to study; its function and anatomy are better resolved than any other cortical region. A deeper understanding of cortical synaptic mechanisms provides insight into processes that go awry during disease. For example, the work proposed here bears directly on a central theme in research on amblyopia, the examination of how abnormal visual experience leads to changes in central processing.